Low Testosterone Associated With Obesity and the Metabolic Syndrome Contributes to Sexual Dysfunction and Cardiovascular Disease Risk in Men With Type 2 Diabetes
- Christina Wang, MD1⇓,
- Graham Jackson, MD2,
- T. Hugh Jones, MD3,
- Alvin M. Matsumoto, MD4,
- Ajay Nehra, MD5,
- Michael A. Perelman, PHD6,
- Ronald S. Swerdloff, MD1,
- Abdul Traish, PHD7,
- Michael Zitzmann, MD8 and
- Glenn Cunningham, MD9
- 1Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California
- 2London Bridge Hospital, London, U.K.
- 3Robert Hague Centre for Diabetes and Endocrinology, Barnsley Hospital, and the Department of Metabolism, University of Sheffield Medical School, Sheffield, U.K.
- 4Geriatric Research, Education and Clinical Center, V.A. Puget Sound Health Care System, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
- 5Department of Urology, Mayo Clinic, Rochester, Minnesota
- 6Departments of Psychiatry, Reproductive Medicine, and Urology, NY Weill Cornell College of Medicine, New York, New York
- 7Department of Urology, Boston University School of Medicine, Boston, Massachusetts
- 8Clinical Andrology/Centre for Reproductive Medicine and Andrology, University Clinics of Muenster, Muenster, Germany
- 9Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, St. Luke’s–Baylor Diabetes Program, Houston, Texas
- Corresponding author: Christina Wang, wang{at}labiomed.org.
Article Figures & Tables
Figures
- Figure 1
Complex multidirectional interactions between testosterone and obesity, metabolic syndrome, and type 2 diabetes mediated by cytokines and adipokines leading to comorbidities such as ED and increased CVD risk. FFA, free fatty acids; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PAI-1, plasminogen activator inhibitor-1.
Tables
- Table 1
Low testosterone is associated with increased mortality in older men
Study design n Follow-up (years) Mortality Hazard ratio (95% CI) Recent studies Retrospective 858 8 All-cause 1.88 (1.34–2.63)* Shores et al. (42) Prospective 794 20 All-cause and CVD 1.40 (1.14–1.71)* 1.38 (1.02–1.85)* Laughlin et al. (45) Prospective 2,314 10 All-cause and CVD 2.29 (1.60–3.26)* Khaw et al. (43) Prospective 1,954 7.2 All-cause and CVD 2.32 (1.38–3.89)* Haring et al. (44) Prospective 930 6.9 All-cause and CVD in men with CVD 2.27 (1.45–3.60)* Malkin et al. (46) ↵*On the basis of recent publications in which the number of subject is >500 and age of the subjects is >60 years.
- Table 2
Randomized trials of testosterone replacement in hypogonadal men with metabolic syndrome or type 2 diabetes
Study Kapoor et al. (55) Heufelder et al. (56) Kalinchenko et al. (57) Jones et al.* (37) Subjects Type 2 diabetes New type 2 diabetes/metabolic syndrome Type 2 diabetes/metabolic syndrome Type 2 diabetes/metabolic syndrome Study design RCT-c NRCT RCT-p RCT-p n 24 32 184 220 Duration (months) 3 12 6 6/12* Medications for diabetes Diet, oral, insulin Naive Diet, oral Diet, oral Baseline serum testosterone (nmol/L) ≤8.6 ≤10.5 ≤6.7 ≤10.2 Testosterone formulation TES injections (200 mg/2 weeks) Testosterone gel (50 mg/day) TU depot injections Testosterone gel (40–80 mg/day) Treatment effects (changes) HOMA-IR −1.7 −0.9 −1.49 −0.54 Fasting glucose (nmol/L) −1.6 −0.3 (AS) ↔ −0.42 (AS) Fasting insulin (mIU/mL) ↔ ↓ ↔ ↓(AS) HbA1c −0.37 −0.80 ND ↔ [−0.45]† Total cholesterol (nmol/L) −0.4 ND ↔ ↔ [−0.13] LDL cholesterol (nmol/L) ↔ ND ↔ ↔‡ HDL cholesterol (nmol/L) ↔ ↑§ ↔ −0.049‡ Triglycerides ↔ ↓ ↔ ↔ Lipoprotein a ND ND ND ↓ BMI ↔ ↔ ↔ ↔ Waist circumference ↓ ↓ ↓ ↔ % Body fat ND ND ND ↔ Blood pressure ↔ ↓‖ ND ↔ ↔, No significant change; ↑, significant increase; ↓, significant decrease; AS, approaching significance (P = 0.05–0.07); ND, not done; NRCT, randomized open label, not placebo-controlled parallel trial; RCT-c, randomized placebo-controlled crossover; RCT-p, randomized placebo-controlled parallel; TES, mixed testosterone esters; TU, testosterone undecanoate depot injections after the first injection followed by another injection at 6 weeks and then injections every 12 weeks. Testosterone gel was dose-adjusted to give total testosterone level >17 nmol/L.
↵*The study by Jones et al. (TIMES2) had no medication changes in the first 6 months unless overriding clinical needs, but medication changes were allowed in the second 6 months for ethical reasons (intention-to-treat group, modified per protocol group where no changes in medications occurred; data not shown).
↵†Significant difference compared with placebo observed after 9 months, but result may be confounded by allowed medication changes.
↵‡Metabolic syndrome subgroup showed significant changes in total cholesterol (−0.34 mmol/L), LDL cholesterol (−0.21 mmol/L), and HDL cholesterol (−0.058 mmol/L).
↵§No figure quoted.
‖Diastolic blood pressure only.
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